The blood-brain barrier (BBB) is primarily formed by brain capillary endothelial cells (BCECs), which are highly specialized endothelial cells with unique morphology, biochemistry, and function. Astrocytic endfeet surround more than 90% of the BCEC abluminal surface and, together with neuronal endings that directly innervate the BCEC, influence the “tightness” and trafficking role of the barrier.
The surface area of the human brain blood microvasculature available for protein/vector/therapeutic transport is ˜20 m2. The microvasculature is so dense that all neuron and glial cells are within a 20 μm proximity (Giaume, C. et al. Nat. Rev. Neurosci. 11:87-99 (2010)); therefore, a protein/vector/therapeutic can potentially reach the entire brain volume. If a substance can be delivered across the BBB or bypass this barrier, systemic delivery via circulation can provide an ideal noninvasive method for rapid and wide distribution of neurotherapeutics throughout the brain.
However, the barrier properties of the BBB formed by the BCECs restrict delivery of almost all neurotherapeutic agents from the blood circulation to the brain. Only small and lipophilic molecules (<0.5 kD) or those that bind to one of the receptors on BCEC can be transported effectively across the BBB (Pardridge, W. Nat. Rev. Drug Discov. 1:131-9 (2002)).